Modification of DNA structure by histone-like proteins appears to be a central regulatory mechanism governing the complex life cycle of Chlamydia trachomatis. Histone H1 homologs are rare among prokaryotes, C. trachomatis possesses two EB specific proteins with primary amino acid sequence homology to eukaryotic H1. These histone homologs, termed Hc1 and Hc2, are expressed only during the late stages of the chlamydial life cycle concomitant with the reorganization of RBs into EBs and appear to play a major role in establishment of nucleoid structure as well as in control of gene expression. Expression of Hc1 in E. coli results in a compaction of the chromatin that ultrastructurally resembles the nucleoid reorganization which occurs late in the chlamydial developmental cycle. Hc2 expression in E. coli also condenses the chromatin although no comparable structure is observed in either EBs or intermediate developmental forms. In contrast to the electron-dense spheres produced by Hc1, Hc2 expression produces nucleoids that have a distinct, coil-like appearance. Hc2 is enriched in isolated nucleoids from Hc2 expressing E. coli and protects the isolated DNA from nucleolytic digestion. Hc1 expression in E. coli is self-limiting and produces a global termination of transcription, translation, and replication at concentrations equivalent to that of chlamydial elementary bodies. We have proposed that association of Hc1 with DNA at levels below that necessary to condense the nucleoid may exert more specific regulatory effects through modification of DNA structure/topology to influence promoter activity and gene expression. Alteration of DNA topology in response to environmental signals appears to play an underlying role in regulation of gene expression in bacteria. Hc1-mediated effects on DNA topology may thus play a significant role in the regulation of gene expression during chlamydial development. Understanding the controlling mechanisms for gene expression and differentiation may suggest unique methods of interrupting parasite replication.